Macrophage targeting: opening new possibilities for cancer immunotherapy

Abstract

Tumour-infiltrating immune cells regulate tumour development and progression either negatively or positively. For example, cytotoxic lymphocytes (CTL) such as CD8⁺ T and natural killer (NK) cells can recognize and eliminate cancer cells, and thereby restrict the tumour growth and metastasis, if they exert full cytotoxicity. In contrast, tumour-infiltrating myeloid cells such as tumour-associated macrophages (TAM) promote the expansion and dissemination of cancer cells depending on their functional states. Given the tumour-killing ability of CTL, the augmentation of CTL-induced antitumour immune reactions has been considered as an attractive therapeutic modality for lethal solid tumours and several promising strategies have emerged, which include immune checkpoint inhibitors, cancer vaccines and adoptive CTL transfer. These immunotherapies are now tested in clinical trials and have shown significant antitumour effects in patients with lymphoma and some solid tumours such as melanoma and lung cancer. Despite these encouraging results, these therapies are not efficient in a certain fraction of patients and tumour types with tumour cell-intrinsic mechanisms such as impaired antigen presentation and/or tumour cell-extrinsic mechanisms including the accumulation of immunosuppressive cells. Several animal studies suggest that tumour-infiltrating myeloid cells, especially TAM, are one of the key targets to improve the efficacy of immunotherapies as these cells can suppress the functions of CD8⁺ T and NK cells. In this review, we will summarize recent animal studies regarding the involvement of TAM in the immune checkpoint, cancer vaccination and adoptive CTL transfer therapies, and discuss the therapeutic potential of TAM targeting to improve the immunotherapies.

Keywords: cancer; immunotherapy; macrophage; tumour immunology.

Figure 1

Potential therapeutic approaches to prevent tumour‐associated macrophage (TAM) ‐mediated immune suppression. Classical monocytes in the blood are recruited to the solid tumours where they differentiate to TAM. The TAM suppress cytotoxicity of CD8⁺ T or natural killer (NK) cells directly via expressing immune suppressive molecules or indirectly via the recruitment of other immune suppressor cells such as regulatory T (Treg) cells. However, TAM can become immune‐activating macrophages in response to certain environmental factors. It is therefore likely that either prevention of TAM accumulation (depletion), alteration of TAM features (reprogramming), or blockade of TAM‐derived immune suppressive molecules (molecular targeting) are attractive approaches to dislodge the TAM‐induced immune suppressive environment in the solid tumours.

Figure 2

Effects of tumour‐associated macrophages (TAM) ‐targeting strategies on efficacy of immune checkpoint inhibitors. Immune checkpoint inhibitor (ICI) enhances CD8⁺ T‐cell cytotoxicity by blocking immune checkpoint pathways via programmed cell death protein 1 (PD1) or cytotoxic T‐lymphocyte‐associated protein 4 (CTLA4) activated by cancer cells and TAM. However, TAM also suppresses CD8⁺ T‐cell functions via checkpoint pathway‐independent mechanisms and limits the efficacy of ICI (a). Several studies suggest that all potential TAM‐targeting approaches, that is TAM depletion (b), TAM reprogramming (c), and targeting functional molecules of TAM (d), can improve the therapeutic efficacy of ICI. The yellow arrow represents cytotoxicity of CD8⁺ T cells.

Figure 3

Opposite effects of macrophage depletion on therapeutic cancer vaccination therapy. Administration of tumour antigen with strong adjuvant or dendritic cells pre‐exposed to antigen activates naive CD8⁺ T cells that exert antitumour ability. However, their cytotoxicity is suppressed by tumour‐associated macrophages (TAM), and hence, pharmacological macrophage depletion, for example treatment with a colony‐stimulating factor 1 receptor (CSF1R) antagonist, enhances efficacy of vaccinations (a). In some cases, however, the activated CD8⁺ T cells alter the phenotype of TAM from immune suppressive to immune‐activating/tumoricidal. Under such situations, macrophage depletion reduces rather than enhances the efficacy of therapeutic cancer vaccination (b). The yellow arrow represents cytotoxicity of CD8⁺ T cells or reprogrammed macrophages.

Figure 4

Improvement of chimeric antigen receptor T (CAR‐T) cell transfer therapy via the removal of tumour‐associated macrophages (TAM) ‐mediated immune suppression. T cells manipulated to express CAR‐T recognize surface protein on cancer cells and exert tumour‐killing activity without prior activation, whereas their functions are restricted by TAM (a). It is reported that genetic manipulation of CAR‐T cells to secrete interleukin‐12 (IL‐12) enhances efficacy of the therapy via reprogramming of TAM to tumoricidal macrophages that express tumour necrosis factor‐α (TNF‐α) (b). In another model, expression of IL‐12 in CAR‐T cells enhances therapeutic potential of CAR‐T cells by depletion of TAM as well as augmentation of cytotoxic capacity of CAR‐T cells (c; left). It is also suggested that expression of CAR against macrophage surface protein (e.g. folate receptor β: FRβ) can deplete TAM, whereas its therapeutic impact on CAR‐T cell cytotoxicity against tumour cells is still not known. The yellow arrow represents cytotoxicity of CD8⁺ T cells or reprogrammed macrophages.